(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (I).
which is known as Iopamidol, is one of the most widely employed non-ionic radiographic contrast agents in the world.
It was first described in GB1472050, where its synthesis by the process outlined in the following Scheme has been reported:

The above process, that is still widely employed industrially, has anyway several drawbacks.
One of them is the introduction of the protected chiral synton (S)-2-(acetyloxy)propanoyl on the 5-amino group at an early stage of the overall process, i.e. before the amidation with 2-amino-1,3-propanediol.
Just introducing this chiral group via reaction of the 5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide with (S)-2-(acetyloxy)propanoyl chloride would lead to the preferential acylation of the more reactive hydroxy groups of the carboxamido substituents, thus causing remarkable wasting of expensive reactant.
WO 00/50385 has recently described a process for the preparation of polyhydroxy compounds (including i.a. iopamidol) comprising the step of deacylating, under acidic conditions, an acylated compound having the formula:
wherein R4 and R5 are optionally acylated dihydroxyalkyl groups, R6 is alkyl and R3 is i.a. a methyl group.
According to WO 00/50385 the acid used in this deacylation reaction is then removed by batch treatment with an acid scavenging resin; an aqueous solution of the thus obtained product is purified by passing through a non-ionic polymeric adsorbent resin; the eluate is concentrated to an oil; and the oil is crystallised from acetonitrile/ethanol or ethanol.
The above method is said to reduce racemization at the chiral carbon that—according to WO 00/50385—occurs whenever basic conditions are employed to remove the R6CO— protecting group of the chiral substituent.
Examples of acyl groups reported in WO 00/50385 are formyl, acetyl, propanoyl, butanoyl, pivaloyl, pentanoyl, trifluoroacetyl, and benzoyl.
For iopamidol, WO 00/50385 describes the preparation of the starting acylated compound through introduction of the R6CO— protected chiral substituent on the 5-amino group of a tetraester of the 5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide. The isolated pentacylated product is then converted into iopamidol by the claimed process that requires deacylation under drastic acidic conditions. More particularly the actual conditions exemplified in WO 00/50385 for iopamidol are heating the pentacetyl derivative at the reflux temperature with hydrochloric acid in methanol for 30 hours.